The classical cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) is the major active constituent extracted from Cannabis sativa. The effects of cannabinoids are due to an interaction with specific high affinity receptors. Presently two Gi/o protein coupled cannabinoid receptors, namely CB1 and CB2, have been characterized in mammals and other organisms. The CB1 receptor is very densely distributed through the central nervous system, and at lower levels in various peripheral tissues, including the myocardium, postgangliomic autonomic nerve terminals, and vascular endothelial and smooth muscle cells as well as the liver, skeletal muscle and adipose tissue (Pacher, et al., Pharmacol. Rev. (2006) 58:389-462; Batkai, et al., Circulation (2004) 110:1996-2002; Bonz, et al., J. Cardiovasc. Pharmacol. (2005) 41:657-664; Mukhopadhyay, et al., J. Am. Coll. Cardiol. (2007) 50:528-536; Rajesh, et al., Am. J. Physiol. Heart Circ. Physiol. (2007) 293:H2210-H2218; Rajesh, et al., Br. J. Pharmacol. (2008) 153:347-357; Mallat, et al. Am. J. Physiol. Gastrointest. Liver Physiol. (2008) 294:9-12; Osei-Hyiaman, et al., J. Clin. Invest. (2005) 115:1298-1305; Engeli, et al., Diabetes (2005) 54:2838-2843; Jeong, et al., Cell. Metab. (2008) 7:227-235; Pagotto, et al., Endocr. Rev. (2006) 27:73-100; Cota, et al., J. Clin. Invest. (2003) 112:423-431).
The CB2 receptor is present in immune and hematopoietic cells and recently has also been identified in the brain, myocardium, liver, and human coronary endothelial and smooth muscle cells (Van Sickle, et al., Science (2005) 310:329-332; Gong, et al., Brain Res. (2006) 1071:10-23; Mukhopadhyay, et al., J. Am. Coll. Cardiol. (2007) 50:528-536; Mallat, et al., Am. J. Physiol. Gastrointest. Liver Physiol. (2008) 294:9-12; Rajesh, et al. Am. J. Physiol. Heart Circ. Physiol. (2007) 293:H2210-2218; Rajesh, et al., Br. J. Pharmacol. (2008) 153:347-357).
Some compounds (cannabinergic ligands) can bind to the CB1 and/or CB2 receptors in an individual or animal. In vitro methods for assaying the ability of a compound to bind to CB1 and/or CB2 receptors are known. Results from the in vitro assay correlate with and predict the in vivo ability of that compound to bind to CB1 and/or CB2 receptors and modulate their function(s). When introduced in an individual or animal some of these cannabinergic ligands can bind to and modulate (activate or deactivate) the CB1 and/or CB2 receptors. Examples of some cannabinergic ligands include N-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) (both endogenous ligands for the cannabinoid CB1 and CB2 receptors), (−)-Δ9-tetrahydrocannabinol (Δ9-THC, the principal bioactive constituent of cannabis preparations and exogenous ligand for the cannabinoid CB1 and CB2 receptors) and other synthetic cannabinergic analogs.
Ligands for the CB1/CB2 cannabinoid receptors, such as (−)-Δ9-tetrahydrocannabinol can bind to and modulate (activate or deactivate) the CB1/CB2 cannabinoid receptors and thereby provide a physiological effect in an individual or animal that is useful to treat a condition in that individual or animal. Conditions that may be treated by modulation of the CB1/CB2 cannabinoid receptors include for example: pain; central pain; peripheral pain; neuropathic pain; neuropathy; inflammatory pain; neurodegenerative diseases including multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease and amyotrophic lateral sclerosis; mental disorders such as schizophrenia and depression; mood disorders; addiction disorders; memory disorders; gastrointestinal motility disorders such as irritable bowel syndrome and diarrhea; dyskinesia; migraine; osteoporosis, osteoarthritis; high blood pressure disease or hypertension; peripheral vascular disease; coronary artery disease; abnormal heart rate; cardiac insufficiency; pulmonary hypertension; ocular hypertension or glaucoma; to prevent or reduce endotoxic shock and hypotensive shock; to modulate appetite; to modulate the immune system; to modulate fertility; to prevent or reduce diseases associated with motor dysfunction such as Tourette's syndrome; to prevent or reduce inflammation; to provide neuroprotection; to produce peripheral vasodilation; to treat epilepsy; to treat nausea such as associated with cancer chemotherapy; AIDS wasting syndrome; to treat several types of cancer as well as other ailments in which cannabinoid system is implicated.